Treatment of human immunodeficiency virus infection (HIV-1) with antiretroviral drugs represents an essential component of strategies to modify the course of HIV disease for the foreseeable future. Zidovudine (ZDV) has been shown to reduce morbidity and prolong survival time in HIV-infected persons. Currently, a standard fixed dose (500-600 mg/day) of ZDV is recommended for all adults but it is not known whether ZDV dosing should be based on body weight. Furthermore, we do not know if the dosage regimen should be individualized based on patient-specific characteristics of ZDV absorption, distribution, metabolism, and elimination, and whether this approach would result in greater efficacy or fewer adverse reactions. The long-term goal of this project is to determine the optimal dosing strategy for antiretroviral agents that ensures maximum benefit. We will begin these investigations with ZDV because it represents the "gold-standard" of therapy. The specific aims of this project are: first, to demonstrate, using minimally invasive strategies, that concentration-controlled ZDV therapy, contrasted to the standard fixed-dose approach, can achieve and maintain a target level of exposure and reduce the variability associated with steady-state concentrations and area-under-the-curve; second, determine the safety and antiviral activity of concentration-controlled vs standard ZDV therapy and employ pharmacodynamic modeling techniques to develop quantitative concentration and effect relationships; and finally, to develop and evaluate predictive models for other antiretroviral agents, such as didanosine. We propose to conduct a randomized, crossover, open-label, outpatient study in 30 HIV-infected individuals using two different ZDV regimens: a fixed dose of 5OO mg/day, and a concentration-controlled regimen designed to maintain a steady-state concentration of O.7 microM. The total duration of this study will be 24 weeks. Participants will be randomized to either the concentration-controlled or standard ZDV regimen for the first 12 weeks, and then crossed over to the alternative regimen for an additional 12 weeks. Study participants will be closely monitored for safety, tolerance, ZDV serum concentrations, virologic and immunologic parameters, opportunistic infections, and progression of HIV- 1 disease. Data analysis will compare the two ZDV dosing regimens in terms of concentrations achieved, safety, antiviral efficacy, and pharmacodynamic relationships. The work proposed in this application will answer several questions concerning our use and understanding of ZDV therapy; however, the knowledge gained and the methods used will be applicable to other antiretroviral drugs. This study represents a significant step in learning whether we can improve upon the rather primitive "treat everyone the same" dosing strategies currently used for nucleoside antiretroviral drugs.